Design of Protease Inhibitors to Target HTLV-1 Human T cell leukemia virus type 1 (HTLV-1) is the first identified human retrovirus that infects millions of people worldwide. HTLV-1 is highly carcinogenic, and infection can lead to life- threatening cancers and disabling inflammatory conditions. A recent major outbreak in Australia, persistent infected populations over the globe, and spread to non-endemic regions with immigration urges immediate action to address this largely neglected disease. Recently, the Global Virus Network Task Force leadership has strongly recommended expanding research on HTLV-1. In stark contrast to the highly related HIV-1, no direct-acting antiviral (DAA) agents have been developed to target HTLV-1 since its discovery almost 40 years ago. Although enzymatically similar, the HTLV-1 protease substrate specificity is quite distinct from HIV-1 protease. This prevents the current HIV-1 protease inhibitors from being effective against HTLV-1, although some have very weak binding. Designing inhibitors to target the substrate envelope of HTLV-1 protease represents the best opportunity for developing a highly potent and robust HTLV-1 inhibitor. Characterization of the substrate envelope will also reveal the molecular basis of substrate specificity for the highly neglected HTLV-1 protease. Translation of our strategies coupled with our extensive experience with HIV-1 will immensely benefit the discovery of small molecule inhibitors against HTLV-1.